Identifying optimal dosing strategies for meropenem in the paediatric intensive care unit through modelling and simulation.

BACKGROUND: Meropenem, a ß-lactam antibiotic commonly prescribed for severe infections, poses dosing challenges in critically ill patients due to highly variable pharmacokinetics. OBJECTIVES: We sought to develop a population pharmacokinetic model of meropenem for critically ill paediatric and young adult patients. PATIENTS AND METHODS: Paediatric intensive care unit patients receiving meropenem 20-40 mg/kg every 8 h as a 30 min infusion were prospectively followed for clinical data collection and scavenged opportunistic plasma sampling. Nonlinear mixed effects modelling was conducted using Monolix®. Monte Carlo simulations were performed to provide dosing recommendations against susceptible pathogens (MIC ≤ 2 mg/L). RESULTS: Data from 48 patients, aged 1 month to 30 years, with 296 samples, were described using a two-compartment model with first-order elimination. Allometric body weight scaling accounted for body size differences. Creatinine clearance and percentage of fluid balance were identified as covariates on clearance and central volume of distribution, respectively. A maturation function for renal clearance was included. Monte Carlo simulations suggested that for a target of 40% fT > MIC, the most effective dosing regimen is 20 mg/kg every 8 h with a 3 h infusion. If higher PD targets are considered, only continuous infusion regimens ensure target attainment against susceptible pathogens, ranging from 60 mg/kg/day to 120 mg/kg/day. CONCLUSIONS: We successfully developed a population pharmacokinetic model of meropenem using real-world data from critically ill paediatric and young adult patients with an opportunistic sampling strategy and provided dosing recommendations based on the patients' renal function and fluid status.

Comparison of 16 Pediatric Acute Respiratory Distress Syndrome-Associated Plasma Biomarkers With Changing Lung Injury Severity.

OBJECTIVES: Pediatric acute respiratory distress syndrome (PARDS) is a source of substantial morbidity and mortality in the PICU, and different plasma biomarkers have identified different PARDS and ARDS subgroups. We have a poor understanding of how these biomarkers change over time and with changing lung injuries. We sought to determine how biomarker levels change over PARDS course, whether they are correlated, and whether they are different in critically ill non-PARDS patients. DESIGN: Two-center prospective observational study. SETTING: Two quaternary care academic children's hospitals. PATIENTS: Subjects under 18 years of age admitted to the PICU who were intubated and met the Second Pediatric Acute Lung Injury Consensus Conference-2 PARDS diagnostic criteria and nonintubated critically ill subjects without apparent lung disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma samples were obtained on study days 1, 3, 7, and 14. The levels of 16 biomarkers were measured using a fluorometric bead-based assay. Compared with non-PARDS subjects, on day 1 PARDS subjects had increased concentrations of tumor necrosis factor-alpha, interleukin (IL)-8, interferon-γ, IL17, granzyme B, soluble intercellular adhesion molecule-1 (sICAM1), surfactant protein D, and IL18 but reduced matrix metalloproteinase 9 (MMP-9) concentrations (all p < 0.05). Day 1 biomarker concentrations and PARDS severity were not correlated. Over PARDS course, changes in 11 of the 16 biomarkers positively correlated with changing lung injury with sICAM1 ( R = 0.69, p = 2.2 × 10 -16 ) having the strongest correlation. By Spearman rank correlation of biomarker concentrations in PARDS subjects, we identified two patterns. One had elevations of plasminogen activator inhibitor-1, MMP-9, and myeloperoxidase, and the other had higher inflammatory cytokines. CONCLUSIONS: sICAM1 had the strongest positive correlation with worsening lung injury across all study time points suggesting that it is perhaps the most biologically relevant of the 16 analytes. There was no correlation between biomarker concentration on day 1 and day 1 PARDS severity; however, changes in most biomarkers over time positively correlated with changing lung injury. Finally, in day 1 samples, 7 of the 16 biomarkers were not significantly different between PARDS and critically ill non-PARDS subjects. These data highlight the difficulty of using plasma biomarkers to identify organ-specific pathology in critically ill patients.

Pharmacokinetic Factors Associated With Early Meropenem Target Attainment in Pediatric Severe Sepsis.

OBJECTIVES: To determine the frequency of early meropenem concentration target attainment (TA) in critically ill children with severe sepsis; to explore clinical, therapeutic, and pharmacokinetic factors associated with TA; and to assess how fluid resuscitation and volume status relate to early TA. DESIGN: Retrospective analysis of prospective observational cohort study. SETTING: PICU in a single academic quaternary care children's hospital. PATIENTS: Twenty-nine patients starting meropenem for severe sepsis (characterized as need for positive pressure ventilation, vasopressors, or ≥ 40 mL/kg bolused fluid), of which 17 were newly escalated to PICU level care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Concentration-time profiles were analyzed using modeling software employing opportunistic sampling, Bayesian estimation, and a population pharmacokinetic model. Time above four times minimum inhibitory concentration (T > 4×MIC), using the susceptibility breakpoint of 1 µg/mL, was determined for each patient over the first 24 hours of meropenem therapy, as well as individual clearance and volume of distribution (Vd) estimates. Twenty-one of 29 patients met a target of 40%T > MIC 4 µg/mL. Reaching TA, vs. not, was associated with lower meropenem clearance. We failed to identify a difference in Vd or an association between the TA group and age, weight, creatinine-based estimated glomerular filtration rate (eGFR), or the amount of fluid administered. eGFR was, however, negatively correlated with overall T > MIC. CONCLUSIONS: Eight of 29 pediatric patients with early severe sepsis did not meet the selected TA threshold within the first 24 hours of meropenem therapy. Higher clearance was associated with failure to meet targets. Identifying patients likely to have higher meropenem clearance could help with dosing regimens.

Aphasia Awareness Among Spiritual Healthcare Providers in the United States.

Spiritual healthcare providers (e.g., chaplains) working in healthcare settings across the United States were surveyed with the goals of (1) understanding their awareness of aphasia (a language disorder affecting reading, writing, verbal communication, and auditory comprehension); (2) determining whether they have received any training in aphasia and what type of training has been received; (3) whether they altered their approach to assessing the spiritual well-being of a person with aphasia; and, (4) what tools were used to augment communication. From a convenience sample of 203 respondents, the results indicated that 96% of respondents had previously heard of aphasia and 85% of respondents correctly identified the definition of aphasia. Seventy-three percent of respondents (N = 128) altered their approach to spiritual well-being assessment due to the aphasia diagnosis. Most respondents did not indicate receiving any formal training related to aphasia.

Population Pharmacokinetic Modeling of Total and Free Ceftriaxone in Critically Ill Children and Young Adults and Monte Carlo Simulations Support Twice Daily Dosing for Target Attainment.

Critical illness, including sepsis, causes significant pathophysiologic changes that alter the pharmacokinetics (PK) of antibiotics. Ceftriaxone is one of the most prescribed antibiotics in patients admitted to the pediatric intensive care unit (PICU). We sought to develop population PK models of both total ceftriaxone and free ceftriaxone in children admitted to a single-center PICU using a scavenged opportunistic sampling approach. We tested if the presence of sepsis and phase of illness (before or after 48 h of antibiotic treatment) altered ceftriaxone PK parameters. We performed Monte Carlo simulations to evaluate whether dosing regimens commonly used in PICUs in the United States (50 mg/kg of body weight every 12 h versus 24 h) resulted in adequate antimicrobial coverage. We found that a two-compartment model best described both total and free ceftriaxone concentrations. For free concentrations, the population clearance value is 6.54 L/h/70 kg, central volume is 25.4 L/70 kg, and peripheral volume is 19.6 L/70 kg. For both models, we found that allometric weight scaling, postmenstrual age, creatinine clearance, and daily highest temperature had significant effects on clearance. The presence of sepsis or phase of illness did not have a significant effect on clearance or volume of distribution. Monte Carlo simulations demonstrated that to achieve free concentrations above 1 µg/ml for 100% of the dosing intervals, a dosing regimen of 50 mg/kg every 12 h is recommended for most patients. A continuous infusion could be considered if the target is to maintain free concentrations four times above the MICs (4 µg/ml).

Multi-omic characterization of pediatric ARDS via nasal brushings.

RATIONALE: While nasal brushing transcriptomics can identify disease subtypes in chronic pulmonary diseases, it is unknown whether this is true in pediatric acute respiratory distress syndrome (PARDS). OBJECTIVES: Determine whether nasal transcriptomics and methylomics can identify clinically meaningful PARDS subgroups that reflect important pathobiological processes. METHODS: Nasal brushings and serum were collected on days 1, 3, 7, and 14 from control and PARDS subjects from two centers. PARDS duration was the primary endpoint. MEASUREMENTS AND MAIN RESULTS: Twenty-four control and 39 PARDS subjects were enrolled. Two nasal methylation patterns were identified. Compared to Methyl Subgroup 1, Subgroup 2 had hypomethylation of inflammatory genes and was enriched for immunocompromised subjects. Four transcriptomic patterns were identified with temporal patterns indicating injury, repair, and regeneration. Over time, both inflammatory (Subgroup B) and cell injury (Subgroup D) patterns transitioned to repair (Subgroup A) and eventually homeostasis (Subgroup C). When control specimens were included, they were largely Subgroup C. In comparison with 17 serum biomarkers, the nasal transcriptome was more predictive of prolonged PARDS. Subjects with initial Transcriptomic Subgroup B or D assignment had median PARDS duration of 8 days compared to 2 in A or C (p = 0.02). For predicting PARDS duration ≥ 3 days, nasal transcriptomics was more sensitive and serum biomarkers more specific. CONCLUSIONS: PARDS nasal transcriptome may reflect distal lung injury, repair, and regeneration. A combined nasal PCR and serum biomarker assay could be useful for predictive and diagnostic enrichment. Trial registration Clinicaltrials.gov NCT03539783 May 29, 2018.

Editor's Choice - Metformin Prescription is Associated with a Reduction in the Combined Incidence of Surgical Repair and Rupture Related Mortality in Patients with Abdominal Aortic Aneurysm.

OBJECTIVES: Currently there is no drug therapy for abdominal aortic aneurysm (AAA) and most previous investigations have focused on imaging rather than clinical outcomes. The aim of this study was to assess whether AAA related clinical events were lower in patients prescribed metformin. METHODS: This was a prospective cohort observational study performed in three cities in Australia, which was designed to study risk factors for clinical events not simply to focus on metformin. Patients with an asymptomatic unrepaired AAA of any diameter ≥30 mm were recruited from hospital outpatient clinics and surveillance programs run at four centres. The main outcome was the requirement for AAA repair or AAA related mortality (AAA events). The association between metformin prescription and AAA events was assessed using Kaplan-Meier analysis and Cox proportional hazard analysis. RESULTS: Patients (1,080) with a mean (SD) initial AAA diameter of 46.1 (11.3) mm were followed for a mean (SD) of 2.5 (3.1) years until an AAA event (n = 454), death (n = 176), loss to follow up (n = 128), or completion of current follow up (n = 322). Patients with diabetes who were prescribed metformin (adjusted HR 0.63, 95% CI 0.44-0.93), but not patients with diabetes who were not prescribed metformin (adjusted HR 1.15, 95% CI 0.83-1.59), had a lower incidence of AAA events compared with those without diabetes. Findings were similar in sensitivity analyses restricted to patients with an initial AAA diameter ≤50 mm and patients with a minimum follow up of six months before an AAA event. CONCLUSIONS: These findings suggest that clinically important AAA events may be reduced in patients with diabetes who are prescribed metformin, but not those with diabetes receiving other treatments. A randomised controlled trial is needed to definitively test whether metformin reduces AAA related clinical events in patients with small AAAs who do not have diabetes.

Pharmacokinetic parameters over time during sepsis and the association of target attainment and outcomes in critically ill children and young adults receiving ceftriaxone.

INTRODUCTION: Early sepsis results in pharmacokinetic (PK) changes due to physiologic alterations. PK changes can lead to suboptimal drug target attainment, risking inadequate coverage from antibiotics like ceftriaxone. Little is known about how ceftriaxone PK and target attainment quantitatively change over time in patients with sepsis or the association between target attainment and outcomes in critically ill children and young adults. METHODS: A retrospective analysis of a prospective study was conducted in a single-center pediatric intensive care unit. Septic patients given at least one ceftriaxone dose (commonly as 50 mg/kg every 12 h) and who had blood obtained in both the first 48 h of therapy (early) and afterwards (late) were included. Normalized clearance and central volume were estimated and compared in both sepsis phases. We evaluated target attainment, defined as concentrations above 1× or 4× the minimum inhibitory concentration (MIC) for 100% of dosing intervals, and investigated the association between target attainment and clinical outcomes. RESULTS: Fifty-five septic patients (median age: 7.5 years) were included. Normalized clearance and central volume were similar in both phases (6.18 ± 1.48 L/h/70 kg early vs. 6.10 ± 1.61 L/h/70 kg late, p = 0.60; 26.6 [IQR 22.3, 31.3] L/70 kg early vs. 24.5 [IQR 22.0, 29.4] L/70 kg late, p = 0.18). Individual percent differences in normalized clearance and central volume between sepsis phases ranged from -39% to 276% and -51% to 212% (reference, late sepsis), respectively. Fewer patients attained the 1× MIC target in late sepsis (82% late vs. 96% early, p = 0.013), which was associated with transition to once daily dosing, typically done due to transfer from the pediatric intensive care unit (PICU) to a lower acuity unit. Failure to attain either target in late sepsis was associated with antibiotic broadening. CONCLUSION: Ceftriaxone PK parameters were similar between early and late sepsis, but there were large individual differences. Fewer patients attained MIC targets in late sepsis and all who did not attain the less stringent target received once daily dosing during this period. The failure to attain targets in late sepsis was associated with antibiotic broadening and could be an area for antibiotic stewardship intervention.

Prevalence and Impact of Pharmacy Students as Patient Care Extenders in Medically Underserved Community Pharmacies.

OBJECTIVE: The objective of this study is to evaluate the prevalence and describe the patient care impact of student pharmacists completing community pharmacy rotations in medically underserved areas (MUAs) in Nebraska. METHODS: A list of pharmacy student advanced pharmacy practice experience placements over a 3-year period were obtained from 2 pharmacy schools in Nebraska and then mapped in relation to MUAs in the state. A mixed-methods approach was used to compare and relate findings of a student-logged patient care activity database and semistructured interviews with pharmacy preceptors of participating students. RESULTS: Pharmacy students were placed in 21 (13%) of 159 identified pharmacies located in MUAs. Pharmacy preceptors felt students improved the quality of patient care provided as a result of more uninterrupted time with the patient. Preceptors also indicated that student presence assists both the student and the practicing pharmacist engage in more patient care services. CONCLUSION: There exists a significant opportunity to utilize advanced pharmacy practice students to extend patient care services and address health-care needs in underserved communities, but student placement in MUAs should be optimized.

Demonstrating Feasibility of an Opportunistic Sampling Approach for Pharmacokinetic Studies of ß-Lactam Antibiotics in Critically Ill Children.

There has been increasing interest in incorporating ß-lactam precision dosing into routine clinical care, but robust population pharmacokinetic models in critically ill children are needed for these purposes. The objective of this study was to demonstrate the feasibility of an opportunistic sampling approach that utilizes scavenged residual blood for future pharmacokinetic studies of cefepime, meropenem, and piperacillin. We aimed to show that opportunistic samples would cover the full concentration-versus-time profiles and to evaluate stability of the antibiotics in whole blood and plasma to optimize future use of the opportunistic sampling approach. A prospective observational study was conducted in a single-center pediatric intensive care unit, where pediatric patients administered at least 1 dose of cefepime, meropenem, or piperacillin/tazobactam and who had residual blood scavenged from samples obtained for routine clinical care were enrolled. A total of 138 samples from 22 pediatric patients were collected in a 2-week period. For all 3 antibiotics, the samples collected covered the entire dosing intervals and were not clustered around specific times. There was high variability in the free concentrations and in the percentage of drug bound to protein. There was less than 15% degradation for meropenem or piperacillin when stored in whole blood or plasma at 4°C after 6 days. Cefepime degraded by more than 15% after 3 days. The opportunistic sampling approach is a powerful and feasible method to obtain sufficient samples to study the variability of drug concentrations and protein binding for future pharmacokinetic studies in the pediatric critical care population.

The Effects of Care Team Roles on Situation Awareness in the Pediatric Intensive Care Unit: A Prospective Cross-Sectional Study.

Improved situation awareness (SA) decreases rates of clinical deterioration in the pediatric inpatient setting. We used a prospective, cross-sectional, observational study to measure interprofessional care team SA for a pediatric intensive care unit (PICU) patients. The resident, bedside nurse, and respiratory therapist for each patient were surveyed regarding high clinical deterioration risk status as defined by clinical criteria identified by the PICU fellow or attending and mitigation plan. From March 2018 to July 2019, we surveyed 400 care team trios caring for 73 high-risk patients. Nurses identified the patient's risk status correctly for 375 of 400 patients (94%), respiratory therapists, 380 (95%; P = .4), and residents, 349 (87%; P = .002). For the 73 high-risk patients, nurses were correct 82% of the time, respiratory therapists, 85%, P = .7, and residents, 67%, P = .04. Interventions targeting resident SA are needed within the PICU, especially for high-risk patients.

Disinfection and the prevention of infectious disease.

This article reviews published literature to determine the role environmental disinfection plays in the prevention of infectious disease. Health benefits from disinfection have been established through studies of applications such as critical instrument sterilization, water treatment, and food production. Guidelines by the Centers for Disease Control and Prevention, the Food and Drug Administration, the Environmental Protection Agency, and the International Scientific Forum on Home Hygiene acknowledge the incidence of disease due to insufficient disinfection and that one of the means for prevention of disease is through proper disinfection. Studies conducted in day care centers, long-term care facilities, and laboratories show that disinfectants containing a variety of active ingredients demonstrated efficacy against a broad spectrum of pathogens and interrupted microbial transmission and that the use of disinfectants results in public health benefits.

Portfolio use and practices in US colleges and schools of pharmacy.

OBJECTIVES: To identify the prevalence of portfolio use in US pharmacy programs, common components of portfolios, and advantages of and limitations to using portfolios. METHODS: A cross-sectional electronic survey instrument was sent to experiential coordinators at US colleges and schools of pharmacy to collect data on portfolio content, methods, training and resource requirements, and benefits and challenges of portfolio use. RESULTS: Most colleges and schools of pharmacy (61.8%) use portfolios in experiential courses and the majority (67.1%) formally assess them, but there is wide variation regarding content and assessment. The majority of respondents used student portfolios as a formative evaluation primarily in the experiential curriculum. CONCLUSIONS: Although most colleges and schools of pharmacy have a portfolio system in place, few are using them to fulfill accreditation requirements. Colleges and schools need to carefully examine the intended purpose of their portfolio system and follow-through with implementation and maintenance of a system that meets their goals.

National Survey of Volunteer Pharmacy Preceptors: effects of region, practice setting, and population density on responses.

OBJECTIVES: To survey volunteer pharmacy preceptors regarding experiential education and determine whether differences in responses relate to such factors as geographic region, practice setting, and population density. METHODS: An online survey was sent to 4396 volunteer experiential preceptors. The survey consisted of 41 questions asking the preceptor to comment on the experiential education environment. Experiential education administrators from 9 schools of pharmacy administered the survey to their volunteer preceptors in all regions (Northeast, Midwest, South, and West) of the United States, in various pharmacy practice settings, and areas of differing population densities. RESULTS: A total of 1163 (26.5%) preceptors responded. Regionally, preceptors in the West disagreed more than those in the Midwest and the South that they had enough time to spend with students to provide a quality experience and also required compensation less often than their counterparts in the Northeast and South. Concerning practice settings, hospital preceptors accepted students from more schools, had greater increases in requests, turned away more students, and spent less time with the students compared to preceptors in other settings. Population density differences reflected that preceptors at urban sites took and turned away more students than those at rural sites. Preceptors from rural areas spent more time with students and felt they were spending enough time with their students to provide quality experiences when compared to other preceptors. CONCLUSIONS: The results of this national volunteer preceptor survey may assist pharmacy school leaders in understanding how location, practice type, and population density affect experiential education, preceptor time-quality issues, and site compensation so they can take necessary actions to improve quality of student practice experiences.

National survey of volunteer pharmacy preceptors.

OBJECTIVES: To survey pharmacy preceptors regarding experiential education and determine the implications of the findings on colleges and schools of pharmacy. METHODS: An online survey was sent to 4,396 experiential sites. The survey instrument consisted of 41 questions regarding the experiential education environment from the preceptor's perspective (eg, experiential load, time-quality issues, compensation, etc). RESULTS: One thousand one hundred sixty-three preceptors responded (26.5%) to the survey. Concerning experiential load, 73% took 2 or more students in the past year and almost half of the sites had to turn placements away. Nearly all preceptors felt that the more time they spent with students, the higher quality the experience, and 20% felt they didn't have enough time to provide a quality experience. Thirty-six percent of respondents chose monetary stipend as the form of compensation they valued most. CONCLUSIONS: This study provides insights into the issues that concern volunteer preceptors and the findings could be used to enhance the quality of experiential education in pharmacy.

A service-learning elective in Native American culture, health and professional practice.

OBJECTIVES: To evaluate the success of an elective course in Native American culture, health, and service-learning in fostering interest in experiences and careers with the USPHS Indian Health Service (IHS), and in shaping reflective practitioners. DESIGN: Students conducted readings, kept reflective journals, and engaged in discussions with Native American and non-Native American speakers. Students orally presented a Native American health issue and spent their fall break in Chinle, Ariz, providing social and healthcare services to the Diné under the supervision of IHS pharmacists. Opportunities for additional IHS experiences were discussed, as was discerning the Creator's call to a professional life of service. ASSESSMENT: Thirteen of 15 students who had completed the service-learning course by January 2007 responded to a brief survey indicating that not only were the course objectives met, but the experiences had a lasting impact on professional mindset and career plans. CONCLUSION: The course had a lasting impact on students' understanding of Native American social and health care issues, and on how they will practice their profession and live their lives.

Using performance-based assessments to evaluate parity between a campus and distance education pathway.

OBJECTIVES: To compare the performance of campus-based students with that of distance students during the first 2 years of a doctor of pharmacy program to evaluate parity between the pathways. METHODS: Twelve cases were created for each year of the program along with performance criteria. The cases were converted into computer-based simulations for programmatic assessment at the end of the 2002-2003 and 2003-2004 school years. All first-professional year (P1) and second-professional year (P2) students participated in the assessments. Overall class means were calculated and used to compare student performances between campus and distance education pathways. RESULTS: Overall scores for the 2003 P1 class were 56.4% for the campus-based students and 62.4% for the distance students, (p = 0.002); overall scores for the 2003 P2 class were 48.8% and 55.5%, respectively (p < 0.0001). The 2004 overall scores for P1 campus and distance students were 59.0% and 65.7%, respectively, (p = 0.001); and for 2004 P2 scores the results were 51.8% and 56.5%, respectively (p = 0.049). CONCLUSIONS: Students receiving their pharmacy education via a distance pathway scored higher on performance-based assessments compared with students receiving their pharmacy education via the traditional campus-based pathway. This indicates that distance students are receiving at least an equivalent curricular experience in the P1 and P2 years compared to that received by campus-based students.